Naturally occurring bone is contains about 70% mineral (nanometer-sized calcium deficiency hydroxyapatite) and about 30% organic matrix (collagen, proteins etc.). Bone loss occurs as results of increased bone destruction (resorption by osteoclastic activity) relative to bone formation (by aging or disease). Both bone resorption and formation occur continuously in the skeleton as part of normal skeletal function. During this process packs of bone are being destroyed and rebuilt in a process called remodeling.
Osteoporosis is a disease characterized by low bone mass leading to an increased frequency of low energy fractures. It is known that osteoporosis is a condition that features loss of the normal density of bone and fragile bone. It leads to literally abnormally porous bone that is more compressible (e.g., spongy) than dense (e.g., brick). This disorder of the skeleton weakens the bone, which leads to an increase in the risk of breaking bones (bone fracture).
Bones that are affected by osteoporosis can fracture with only a minor fall or injury that normally would not cause a bone fracture. The fracture can be in the form of cracking (as in a hip fracture), or collapsing (as in a compression fracture of the vertebrae of the spine). The spine, hips, and wrists are common areas of osteoporosis-related bone fractures, although osteoporosis-related fractures can also occur in almost any skeletal bone area.
Among fractures encountered in osteoporosis, vertebral fractures must be taken into account because they are frequent (about 16% of postmenopausal women) and lead to back pain, disability and decreased height.
Bisphosphonates, which are analogues of naturally occurring pyrophosphate that contain a carbon instead of an oxygen atom, are widely used in the treatment of osteoporosis in order to inhibit osteoclastic bone resorption. Bisphosphonates have been observed to preferentially bind to bone mineral in areas that are actively undergoing remodeling. After desorption in bone, bisphosphonates are liberated again only when the bone is resorbed (by osteoclasts). The most common adverse event with bisphosphonate treatment is gastrointestinal disturbance, including, e.g., pain, diarrhea, and abdominal discomfort. Given that treatment for osteoporosis is typically long term, compliance and tolerability (without side effect) are important.
Despite the fact that traditional approaches (mostly based on non-surgical therapies as a preventive measure) have been shown to be ineffective in alleviating pain and correcting spinal deformity, the minimally invasive treatment of vertebral compression fracture (VCF) remains under-developed. Currently, vertebroplasty is performed by percutaneously injecting (by minimally invasive surgery (MIS)) a bone substitute material (BSM) into the vertebral bodies under fluoroscopic and/or computed tomography guidance. A related treatment, kyphoplasty, includes an attempt to expand the vertebra with an inflatable balloon prior to the injection of a BSM. Kyphoplasty is an effective treatment for painful osteoporotic compression fractures, however, patients who undergo kyphoplasty procedure should be informed of the significant risk of adjacent-level fractures over the next 60 days. The reason for this association is unclear, but may occur because cement augmentation at one vertebral level places further stress on adjacent levels.
Typically, a MIS technique allows for the same outcomes as conventional (open) surgery, but with additional benefits that include, e.g., the avoidance of open invasive surgery in favor of closed (tiny incision) or local surgery, a reduction in surgical complications (muscle stripping, blood loss, etc.), a reduction in operative trauma (by soft tissue preservation) with less postoperative pain, a reduction in patient hospitalization time and, consequently, a significant reduction in costs, an increase in the speed of functional return to daily activities, a shorter recovery time (a few months instead of a year), and a few cosmetically tiny scars rather than one large scar.
There are an estimated 800,000 vertebral fractures from osteoporosis every year according to the U.S. National Osteoporosis Foundation, and about 200,000 of these are treated surgically. The vertebrae compression fracture market is estimated at $160 million (in 2007) with the potential to reach $750 million as surgery continues to grow as the standard of care for the condition. In 2004, the global market for minimally invasive VCF treatments, including Kyphoplasty and Percutaneous Vertebroplasty (PV), was valued at more than $250 million.
The current product in today's market used for vertebroplasty indication is a decades-old, non-bioresorbable, and non-remodeling polymethylmethacrylate (PMMA) cement, which is injected in the vertebral body for pain relief and to strengthen weakened vertebral bone. PMMA cement is remarkably strong and does not deteriorate over time, yet it also does not integrate into bone. Moreover, the high compression strength of PMMA can cause adjacent vertebral body fractures by exerting high non-compliant forces on the adjacent occurring adjacent fractures.
In 2007, Health Canada issued information related to serious complications associated with the use of PMMA cement in vertebroplasty and kyphoplasty procedures. Among these complications are the following: death due to sudden blood pressure drop that may be related to the release of the PMMA monomer (leaching effect) into the vascular system, PMMA extravasations into the spinal canal leading to neurologic deficit, with compression of the spinal cord and/or nerve roots, new fractures, usually of adjacent non-augmented vertebrae, and pulmonary embolism due to PMMA.
Unlike PMMA, calcium phosphate cement (CPC), when delivered into the bone, is acted upon by osteoblasts and osteoclasts in the residual trabecular bone and can be remodeled into bone. With its lower compressive strength, CPC also causes less stiffness of the vertebral body. CPC can also integrate into the trabecular bone structure and can promote bone restoration.
There exists a need for compositions that can be used in kyphoplasty and vertebroplasty applications that avoid the complications associated with PMMA cement compositions.